Multiple life-style factors are likely to play a role in the regulation of breast cancer risk. Special attention has been paid to the possible protective effects of dietary soy and fiber, and to the role of putative chemopreventive compounds present in these diets. Recent studies in humans and experimental models suggest that early life dietary exposures are of importance, and regulate breast cancer risk in adulthood. Alterations in estrogen signaling during development influence breast maturation and/or differentiation, and may influence the hormone sensitivity, proliferative activity and, eventually, susceptibility to develop breast cancer during adult life. Estrogen receptors (ERs) are among the major factors that regulate the proliferative activity, differentiation and tumorigenesis in breast tissue. It is possible that the ER expression patterns are, at least partly, determined by the hormonal milieu during development. The major objective of this project is to identify dietary factors that influence ER expression patterns and ER signaling on long-term, resulting in alterations in proliferative activity and/or differentitiation. Special emphasis will be on the ER-subtype-specific effects, as the two ERs (ERalpha and ERbeta) are known to regulate proliferative activity differently. We will focus in two major classes of plant-derived compounds, isoflavonoids and lignans. Both are commonly present in human diets, possess hormonal activity, and influence the development or growth of experimental mammary tumors. The model compounds will be genistein (GEN), the major isoflavonoid present in soy, and enterolactone (ENL), the major mammalian metabolite of plant-derived lignans. Specifically, we will determine if: 1) early life exposure to GEN or ENL will cause permanent alterations in ER subtype expression patterns, epithelial proliferation and differentiation, and mammary tumorigenesis; 2) the altered ER expression pattern is associated with altered proliferative activity and/or changes in differentiation; 3) the effect of GEN or ENL is mediated in ER-subtype-specific manner. First, we will expose rats and mice to dietary GEN or ENL in utero or prepubertally, and record effects in early and late puberty, and adulthood. In order to investigate the specific roles of ER subtypes, we will use breast cancer cells with inducible ER expression, and ER-deficient (ERKO and BERKO) mice.